Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors

• ClinicalTrials.gov Identifier: NCT04985604
• Recruitment Status: Recruiting
• First Posted: August 2, 2021
• Last Update Posted: March 29, 2024
• Sponsor: Day One Biopharmaceuticals, Inc.
• Information provided by (Responsible Party): Day One Biopharmaceuticals, Inc.

Tracking Information

• First Submitted Date: June 23, 2021
• First Posted Date: August 2, 2021
• Last Update Posted Date: March 29, 2024
• Actual Study Start Date: July 15, 2021
• Estimated Primary Completion Date: July 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 22, 2023)

• Phase 1b: Determine the safety of tovorafenib in combination with other therapies [ Time Frame: Up to 48 months ]
  Incidence and severity of adverse events
• Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies [ Time Frame: Up to 48 months ]
  Incidence and severity of adverse events
• Phase 2: Evaluate the efficacy of tovorafenib monotherapy or in combination with other therapies [ Time Frame: Up to 48 months ]
  Overall response rate (ORR) as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Original Primary Outcome Measures (submitted: July 30, 2021)

Evaluate the efficacy of DAY101 [ Time Frame: Up to 48 months ]

Overall response rate (ORR) as assessed by proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by RECIST version 1.1

Current Secondary Outcome Measures (submitted: June 22, 2023)

• Phase 1b: Assess efficacy of tovorafenib in combination with other therapies [ Time Frame: Up to 48 months ]
  Duration of response (DOR) in patients with best overall response of CR or PR
• Phase 1b & 2: Assess additional efficacy parameters of tovorafenib alone and in combination with other therapies [ Time Frame: Up to 48 months ]
  Duration of progression-free survival (PFS) and overall survival (OS)
• Phase 1b & 2: Characterize tumor responses observed with tovorafenib alone and in combination with other therapies [ Time Frame: Up to 48 months ]
  Time to response (TTR) in patients with best overall response of CR or PR; and comparing the DOR in patients with CR or PR with the DOR observed with the immediate prior line of anticancer treatment
• Phase 1b & 2: Characterize the pharmacokinetic (PK) profile of tovorafenib alone and in combination with other therapies [ Time Frame: Up to 48 months ]
  Measure plasma concentration of tovorafenib
• Phase 1b & 2: Characterize the pharmacodynamic (PD) profile of tovorafenib alone and in combination with other therapies [ Time Frame: Up to 48 months ]
  Evaluate changes from baseline of phosphorylated ERK and other relevant biomarkers
• Phase 2: Assess the safety and tolerability of tovorafenib as monotherapy, or in combination with other therapies [ Time Frame: Up to 48 months ]
  Incidence and severity of adverse events

Original Secondary Outcome Measures (submitted: July 30, 2021)

• Assess the safety and tolerability of DAY101 [ Time Frame: Up to 48 months ]
  Type, incidence, and severity of treatment-emergent adverse events and laboratory abnormalities
• Assess additional efficacy parameters of DAY101 [ Time Frame: Up to 48 months ]
  Duration of response (DOR) in patients with best overall response of CR or PR
• Assess additional efficacy parameters of DAY101 [ Time Frame: Up to 48 months ]
  Duration of progression-free survival (PFS)
• Characterize tumor responses observed with DAY101 [ Time Frame: Up to 48 months ]
  Time to response (TTR) in patients with best overall response of CR or PR; and comparing the DOR in patients with CR or PR with the DOR observed with the immediate prior line of anticancer treatment
• Characterize the pharmacokinetic (PK) profile of DAY101 [ Time Frame: Up to 48 months ]
  Measure plasma concentration of DAY101
• Characterize the pharmacodynamic (PD) profile of DAY101 [ Time Frame: Up to 48 months ]
  Evaluate changes from baseline of phosphorylated ERK and other relevant biomarkers

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors
• Official Title: A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination With Other Therapies for Patients With Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations
• Brief Summary: This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent, progressive, or refractory melanoma or other solid tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway.

Detailed Description

Study DAY101-102 (master study) and sub-studies will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period where survival, status and subsequent anticancer therapies are collected.

Tovorafenib will be evaluated alone or combined with a different targeted therapy in each sub-study. The Phase 1b part of each applicable sub-study will evaluate the safety of the combination and select the dose for the Phase 2 part. The Phase 2 part of each sub-study will evaluate anti-tumor activity.

(Closed to Enrollment) Substudy A will enroll patients with recurrent or progressive melanoma or other solid tumors with BRAF fusion or CRAF/RAF1 fusions or amplification.

Substudy B will enroll patients with recurrent or progressive melanoma or other solid tumors with alterations in the key proteins of the MAPK pathway.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Melanoma
• Solid Tumor
• CRAF Gene Amplification
• RAF1 Gene Amplification
• BRAF Gene Fusion
• BRAF Fusion
• CRAF Gene Fusion
• CRAF Fusion
• RAF1 Gene Fusion
• RAF1 Fusion
• Thyroid Cancer, Papillary
• Spitzoid Melanoma
• Pilocytic Astrocytoma
• Pilocytic Astrocytoma, Adult
• Non Small Cell Lung Cancer
• Non-Small Cell Adenocarcinoma
• Colorectal Cancer
• Pancreatic Acinar Carcinoma
• Spitzoid Malignant Melanoma
• Bladder Cancer
• Bladder Urothelial Carcinoma
• MAP Kinase Family Gene Mutation
• RAS Mutation
• RAF Mutation
• MEK Mutation

Intervention

• Drug: Tovorafenib
  Tovorafenib tablet for oral use.
• Drug: Pimasertib
  Pimasertib capsule for oral use.

Study Arms

• Experimental: Arm #1 (Closed to Enrollment)
  Tovorafenib monotherapy
  Intervention: Drug: Tovorafenib
• Experimental: Arm #2
  Tovorafenib plus pimasertib
  Interventions:

  • Drug: Tovorafenib
  • Drug: Pimasertib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 25, 2022): 168
• Original Estimated Enrollment (submitted: July 30, 2021): 43
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: July 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Signed informed consent by patients ≥ 18 years of age and, assent for patients ≥ 12 up to < 18 years of age
• Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1)
• Archival tumor tissue (preferably less than 3 years old) or fresh tumor tissue for correlative studies is required
• If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging

(Closed to Enrollment) Substudy A-specific inclusion criterion:

• Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a concurrent BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplification through a tumor or liquid biopsy as assessed by genomic sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another clinically accepted molecular diagnostic method recognized by local laboratory or agency.

Substudy B-specific inclusion criterion:

• Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a concurrent MAPK pathway alteration (genomic alterations in RAS, RAF, MEK, or NF1) through a tumor or liquid biopsy as assessed by genomic sequencing, PCR, FISH, or another clinically accepted molecular diagnostic method recognized by local laboratory or agency.

Exclusion Criteria:

• Known presence of concurrent activating mutation
• Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

(Closed to Enrollment) Substudy A-specific exclusion criterion:

• Prior therapy of any RAS- RAF-, MEK-, or ERK-directed inhibitor therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Day One Biopharmaceuticals; 650-484-0899; clinicaltrials@dayonebio.com

• Listed Location Countries: Australia, Belgium, Canada, France, Korea, Republic of, Spain, United States

Administrative Information

• NCT Number: NCT04985604
• Other Study ID Numbers: DAY101-102
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Day One Biopharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Day One Biopharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Day One Biopharmaceuticals, Inc.
• Verification Date: March 2024